Skin cancer rates have risen dramatically in the U.S. over the past 25 years and there is a virtual epidemic of both non-melanoma skin cancer (NMSC) and melanoma in the Southwest. Approximately 40% of all cancers in the U.S. diagnosed are NMSC and more than one million new cases are estimated for each year. Melanoma will account for approximately 54,200 new cases in 2003. The incidence and mortality rates for melanoma are increasing more rapidly than any other invasive cancer. The overall goal of this Chemoprevention of Skin Cancer Program Project is to develop new strategies to eradicate intraepithelial neoplasias (lENs) in the skin and dramatically reduce the risk of melanoma and NMSC. Our multilevel basic, translational, and clinical research program of rational drug development to address this increasingly dangerous public health problem will include: 1) preclinical studies of molecular targets essential to UVA and UVB signal transduction identified in human cell lines and unique mouse models of NMSC and melanoma; 2) basic and translational research studies utilizing array-based CGH and cDNA analyses in human skin biopsy samples to identify genes altered in defined NMSC and melanoma carcinogenesis pathways; 3) preclinical toxicology to identify and quantitate dose-limiting toxicities, measure skin and systemic uptake and generate novel chemopreventive agent and prodrug formulations for preclinical and clinical administration; 4) clinical studies to cross validate molecular targets for chemoprevention agent development between mouse and human models of UVB and UVA skin carcinogenesis; 5) clinical studies including histopathologic, karyometric and biomarker analysis (molecular targets identified in Projects I, II, and III) to evaluate efficacy of chemoprevention agents; and 6) sequential phase I, Ila and lib randomized, double-blinded, placebo controlled skin cancer prevention studies of topically administered chemopreventive agents and prodrugs with modulatory activity in the UVB and UVA signal transduction cascade and in animal models of NMSC and melanoma. To successfully accomplish these specific aims, we have assembled a highly integrated group of basic, preclinical, and clinical scientists from five universities and one research institute, the majority of whom have been working together efficiently and cohesively to conquer the major public health burden of skin cancer for two decades. These research scientists have developed a highly integrated, interactive and hypothesis-driven research proposal that has been designed so that all four Projects and Core services depend on each other scientifically and operationally, and ultimately, will lead to the development of clinically useful primary and secondary skin cancer prevention strategies.